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Microbial Control of Host Intercellular Communication

宿主细胞间通讯的微生物控制

基本信息

批准号：
10661500
负责人：
REBECCA L LAMASON
金额：
$ 30.56万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661500
关键词：
Acceleration Actins Adhesions Bacteria Binding Biological Biology Buffers CAV1 gene CAV2 gene Cardiovascular Diseases Caveolae Caveolins Cell Communication Cell physiology Cell-Cell Adhesion Cells Cellular biology Communication Communications Media Complex Cytoskeleton Development Disease Endocytosis Eukaryotic Cell Genes Goals Health Homeostasis Human Image Immunology Intercellular Junctions Life Listeria Listeria monocytogenes Malignant Neoplasms Mechanical Stress Mechanics Mediating Membrane Microbe Microscopy Molecular Molecular Probes Organelles Organism Pathway interactions Polymers Process Protein Dynamics Proteins Quantitative Microscopy RNA Interference RNA interference screen Regulation Role Shapes Signal Transduction Small Interfering RNA Structure Tail Testing Tissues Work cell fixing cell motility host-microbe interactions human disease human tissue improved innovation insight intercellular communication knock-down mechanical signal mechanotransduction microbial novel pathogenic bacteria recruit response spatiotemporal tool

项目摘要

PROJECT SUMMARY/ABSTRACT Multicellular organisms use intercellular communication to coordinate cell function and maintain tissue homeostasis. Recent work suggests that this communication is driven in part by the exchange of organelles (via trans-endocytosis) and mechanical cues directly across cell-cell junctions. Dysregulation of this communication leads to cancer and cardiovascular diseases. Despite its importance, we lack a fundamental molecular understanding of how intercellular communication occurs because of the limited number of cell biological tools capable of probing the molecular mechanisms at cell-cell contacts. This proposal seeks to elucidate the regulatory mechanisms of the pathways thought to control intercellular communication by studying how they are manipulated when under microbial control. The bacterium Listeria monocytogenes disseminates through human tissues using a process called cell-to-cell spread, which is a vesicular-mediated form of intercellular exchange that mimics host trans-endocytosis. Listeria spreads from cell to cell by mobilizing the host’s actin cytoskeleton for intracellular motility and transport to the cell-cell junction. Once at the junction, it pushes against the membrane and forms a double-membrane protrusion that is engulfed by a neighboring cell. Studying this distinctive spreading process will allow us to examine several outstanding cell biological questions. First, are specific endocytic pathways used at cell-cell junctions to engulf large cargo like microbes? Second, are mechanically-sensitive membrane domains or membrane curvature proteins activated as Listeria pushes against the junction during spread? To answer these questions, we used a high-content, image-based siRNA screen to test if Listeria requires host intercellular communication pathways during spread. We discovered that the endocytic and mechanoresponsive caveolar proteins CAV1, CAV2, and PACSIN2 promote Listeria spread. We also revealed a putative role for 19 other host proteins, including those that regulate membrane curvature, trans- endocytosis, and adhesion. Our preliminary findings suggest the overall hypothesis that Listeria subverts multiple intercellular communication pathways to promote cell-to-cell spread. In Aim 1, we will determine how PACSIN2 and caveolins coordinate their activities to promote the engulfment stage of cell-to-cell spread. In Aim 2, we will reveal which of the remaining hits regulate Listeria spread specifically, how they function, and if they work independently or together with caveolae. In the end, our proposed studies will improve our fundamental understanding of host-microbe interactions and basic cell biology, and may uncover how intercellular communication goes awry in human disease.

项目总结/文摘